Hetero-Diels-Alder reactions of homochiral 1,2-diaza-1,3-butadienes with diethyl azodicarboxylate under microwave irradiation. Theoretical rationale of the stereochemical outcome

Article abstract of DOI:10.1021/jo990442x

The stereoselective normal electron demand Diels-Alder reactions of chiral 1,2-diaza-1,3-butadienes, derived from acyclic carbohydrates having different configurations (1-6), with diethyl azodicarboxylate (DEAD) are disclosed. Reactions proceed slowly in

Full text of DOI:10.1021/jo990442x

J . Org. Chem. 1999, 64, 6297-6305
6297
Heter o-Diels-Ald er Rea ction s of Hom och ir a l
1,2-Dia za -1,3-bu ta d ien es w ith Dieth yl Azod ica r boxyla te u n d er
Micr ow a ve Ir r a d ia tion . Th eor etica l Ra tion a le of th e
Ster eoch em ica l Ou tcom e†
Mart´ın Avalos, Reyes Babiano, Pedro Cintas, Fernando R. Clemente, J ose´ L. J ime´nez,*
J uan C. Palacios, and J uan B. Sa´nchez
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Extremadura,
E-06071 Badajoz, Spain
Received March 11, 1999
The stereoselective normal electron demand Diels-Alder reactions of chiral 1,2-diaza-1,3-butadienes,
derived from acyclic carbohydrates having different configurations (1-6), with diethyl azodicar-
boxylate (DEAD) are disclosed. Reactions proceed slowly in benzene solution at room temperature,
but are greatly accelerated by microwave irradiation to form the corresponding functionalized
1,2,3,6-tetrahydro-1,2,3,4-tetrazines (7-18) in good yields. The observed stereoselectivity is markedly
dependent on the relative stereochemistry at C-1′,2′. Thus, 1,2-diazoalkenes derived from per-O-
acylated sugars having threo configuration at C-1′,2′ give tetrazines with a high facial selectivity,
whereas those having erythro configuration at C-1′,2′ afford products in lower diastereomeric ratios.
The facial diastereoselection has been rationalized by a PM3 computational study. These results
prove that in the transition structures (TSs) the reacting azoalkene exhibits formal negative charges
at C-3 and N-2, the former being of greater magnitude, while the heterodienophile displays a partial
positive charge at the substituent attached to the nitrogen atom. Accordingly, a stabilizing
electrostatic interaction will only occur in TSs involving an endo orientation of the azodicarboxylate
in its approach to the azadiene, a fact consistent with the experimental observations.
In tr od u ction a n d Ba ck gr ou n d
catalysts. In this context, carbohydrate-based cycloaddi-
tions represent an attractive and emerging approach in
organic synthesis.4 This strategy combines the powerful
stereoselection provided by a cycloadditive process along
with the stereodirecting effect of an appropriate sugar
template.
In recent years, our research group has reported on
all-carbon and heteroatom cycloadditions from carbohy-
drates, either Diels-Alder or 1,3-dipolar reactions.5
The Diels-Alder reaction still remains an active
research field and a crucial key step in a wide variety of
natural product syntheses.1 For practitioners of this
protocol and for synthetic chemists in general, it is
probably the most powerful construction process in
organic synthesis. Few reactions can compete with the
Diels-Alder reaction. The importance and usefulness of
the Diels-Alder reaction stem from its unique charac-
teristics: high regio- and stereoselectivity, formation of
two new carbon-carbon bonds, and potentially, four new
stereogenic centers. A useful variation involves the use
of heterodienes or -dienophiles, the so-called hetero-
Diels-Alder reaction, which represents an elegant and
versatile procedure in the preparation of noncarbogenic
systems.2 In particular, the process enables the synthesis
of biologically important nitrogen- and oxygen-containing
heterocycles hitherto inaccessible or difficult to achieve
by using standard methodology.3
(2) (a) Boger, D. L. Tetrahedron 1983, 39, 2869-2939. (b) Attanasi,
O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986, 18, 301-327. (c) Boger,
D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Academic Press: San Diego, 1987. (d) Boger, D. L. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette,
L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 4.3. (e)
Barluenga, J .; Toma´s, M. Adv. Heterocycl. Chem. 1993, 57, 1-80. (f)
Boger, D. L. J . Heterocycl. Chem. 1996, 33, 1519-1531. (g) Fringuelli,
F.; Piermatti, O.; Pizzo, F. In Targets in Heterocyclic Systems.
Chemistry and Properties; Attanasi, O., Spinelli, D., Eds.; Italian
Chemical Society: Rome, 1997; Chapter 2.
(3) (a) Boger, D. L. Chem. Rev. 1986, 86, 781-793. (b) Kametani,
T.; Hibino, S. Adv. Heterocycl. Chem. 1987, 42, 245-333. (c) Boger, D.
L. Chemtracts: Org. Chem. 1996, 9, 149-189. (d) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1-120.
(4) (a) Cycloaddition Reactions in Carbohydrate Chemistry; Giuliano,
R. M., Ed.; ACS Symposium Series No. 494; American Chemical
Society: Washington, D. C., 1992. (b) Kunz, H.; Ru¨ck, K. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 336-358. (c) Hultin, P. G.; Earle, M. A.;
Sudharshan, M. Tetrahedron 1997, 53, 14823-14870.
(5) (a) Avalos, M.; Babiano, R.; Cintas, P.; J ime´nez, J . L.; Molina,
M. M.; Palacios, J . C.; Sa´nchez, J . B. Tetrahedron Lett. 1991, 32, 2513-
2516. (b) Avalos, M.; Babiano, R.; Dia´nez, M. J .; Espinosa, J .; Estrada,
M. D.; J ime´nez, J . L.; Lo´pez-Castro, A.; Me´ndez, M. M.; Palacios, J . C.
Tetrahedron 1992, 48, 4193-4208. (c) Areces, P.; Avalos, M.; Babiano,
R.; Gonza´lez, L.; J ime´nez, J . L.; Me´ndez, M. M.; Palacios, J . C.
Tetrahedron Lett. 1993, 34, 2999-3002. (d) Avalos, M.; Babiano, R.;
Cintas, P.; Higes, F. J .; J ime´nez, J . L.; Palacios, J . C.; Silva, M. A. J .
Org. Chem. 1996, 61, 1880-1882. (e) Avalos, M.; Babiano, R.; Cabanil-
las, A.; Cintas, P.; Higes, F. J .; J ime´nez, J . L.; Palacios, J . C. J . Org.
Chem. 1996, 61, 3738-3748.
The stereodifferentiating characteristics of the Diels-
Alder reaction can be profitably enhanced if cycloaddi-
tions are performed on chiral precursors or with chiral
† Dedicated respectfully to the memory of Michael J . S. Dewar
(1918-1997), who taught us the usefulness of computational chemistry
through his “semiempirical” life.
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990. (b) Fringuelli, F.; Taticchi, A. Dienes
in the Diels-Alder Reaction; Wiley: New York, 1990. (c) For
a
comprehensive treatment of cycloaddition reactions: Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, pp 1-673. (d) For a compre-
hensive series on theory and applications of cycloadditions: Advances
in Cycloaddition; Curran, D. P., Ed.; J AI Press: Greenwich, CT, Vol.
1, 1988; Vol. 2, 1990; Vol. 3, 1993; Vol. 4, 1996. (e) Dell, C. P. J . Chem.
Soc., Perkin Trans. 1 1998, 3873-3905.
10.1021/jo990442x CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/04/1999

6298 J . Org. Chem., Vol. 64, No. 17, 1999
Avalos et al.
These cycloadditions with sugar-derived substrates have
potential value for access to enantiomerically pure polysub-
stituted heterocycles. As part of our broad program
concerned with asymmetric cycloadditions employing
acyclic unsaturated sugars as dienes, we describe here
the results of a new study of asymmetric hetero-Diels-
Alder reactions of 1-aryl-1,2-diaza-1,3-butadienes (1-6)
with diethyl azodicarboxylate (DEAD) in order to expand
and generalize the synthetic approach to nitrogen het-
erocycles. These crystalline precursors, having different
carbon side chains of defined and controllable absolute
stereochemistry, are readily accessible from the corre-
sponding sugar hydrazones.6 Preliminary results were
reported a few years ago,5a but herein we describe novel
and optimized procedures which enhance the versatility
still further. In addition, theoretical data full corroborate
the experimental findings of diastereofacial selectivity.
Reactions with DEAD were conducted initially in
benzene solutions at room temperature. Significantly long
reaction times (∼30 days) were usually required for
completion. Alternatively, these processes could be run
at reflux to effect the aza-Diels-Alder addition in shorter
reaction times, but the mixtures were accompanied by
unidentified side products. Realizing that Diels-Alder
reactions are sensitive to thermal and pressure effects,
we then turned our attention to nonconventional activa-
tion methods such as microwaves8 or ultrasound.9 Ul-
trasonic irradiation in a bath operating at ∼20 kHz gave
much cleaner reactions, although a few days are still
required for completion. When reactions were carried out
without solvent (“dry-media reactions”) using a 1:2.5
azoalkene-DEAD molar ratio and irradiated with fo-
cused microwaves,10 the reaction partners gave the
corresponding adducts (7-18) within 6 h, and remark-
ably, without byproducts. It is noteworthy that both
yields and selectivities were identical to those obtained
in benzene solution. In all cases, tetrahydro-1,2,3,4-
tetrazines were isolated with excellent overall yields,
ranging from 80 to 96%, as a mixture of (6R)- and (6S)-
diastereomers as evidenced by 400-MHz NMR analyses
of the crude mixtures (Scheme 1). Such stereoisomers
could further be separated by chromatography and/or
crystallization. Attempts to purify the minor isomers 13
and 14 have not yet been successful. The products thus
obtained in a single synthetic operation are chiral,
densely functionalized polynitrogen rings. These partially
reduced 1,2,3,4-tetrazines, which have been previously
known,11 are also potential heterodienophiles. The struc-
turally related 1,2,4,5-tetrazines may participate in
[4 + 2] cycloadditions with electron-rich dienophiles as
recognized by Boger and his group.12
Chiral 1,2-diazoalkenes bearing an acyclic chain of
D-arabino configuration (1-4) reacted with high stereo-
differentiation, while heterodienes either with D-lyxo (5)
or D-erythro (6) configurations gave a lower discrimina-
tion between both diastereomers (Table 1).
Resu lts a n d Discu ssion
Heter o-Diels-Ald er Rea ction s. Our initial experi-
ments to explore the cycloadditive chemistry of sugar 1,2-
diazadienes were unfruitful and discouraged further
attempts. The apparent inertness of these heterodienes,
compared with simpler diazadienes,2 was evidenced by
reaction failures with reactive dienophiles such as dim-
ethyl acetylenedicarboxylate (DMAD), N-sulfonylimine,
isocyanates, and isothiocyanates. Gratifyingly, success
came with both benzo- and naphthoquinone as described
in our preliminary study.5a Reactions with quinonoid
dienophiles did not afford significant yields of cycload-
ducts (15-30%), due to omnipresent tarry side products,
presumably quinone polymers. However, these unprec-
edented reactions proceeded with high facial diastereo-
selectivity, and structures of major adducts were deter-
mined by NMR spectroscopy.
Concerning the reactivity toward DEAD, the synthetic
results and an analysis of the stereochemical outcome
far exceeded our expectations. Cycloadducts were ob-
tained stereoselectively, and the isomer ratios varied
significantly depending on the structure of the hetero-
diene. The results allow evaluation of the stereodirecting
effects of sugar chains. With a few exceptions,7 these
comparisons have not been reported in previous studies
of carbohydrate-based cycloadditions.
Str u ctu r a l Deter m in a tion . The structures of cy-
cloadducts 7-12 and 15-18 were supported by their
spectroscopic data and elemental analyses. Some oily
samples gave no satisfactory combustion analyses or
high-resolution mass spectra, although they were chro-
matographically homogeneous (TLC) and characterized
1
by high-resolution H and 13C NMR in an unambiguous
(7) (a) Franck, R. W. In Cycloaddition Reactions in Carbohydrate
Chemistry; Giuliano, R. M., Ed.; ACS Symposium Series No. 494;
American Chemical Society: Washington, D. C., 1992; pp 24-32. (b)
Giuliano, R. M.; J ordan, A. D., J r.; Gauthier, A. D.; Hoogsteen, K. J .
Org. Chem. 1993, 58, 4979-4988. (c) Shing, T. K. M.; Zhong, Y.-L.;
Mak, T. C. W.; Wang, R.-J .; Xue, F. J . Org. Chem. 1998, 63, 414-415.
(8) For recent reviews on microwave-induced reactions: (a) Caddick,
S. Tetrahedron 1995, 51, 10403-10432. (b) Loupy, A.; Petit, A.;
Hamelin, J .; Texier-Boullet, F.; J acquault, P.; Mathe´, D. Synthesis
1998, 1213-1234.
(9) For a comprehensive survey on ultrasound-assisted cycloaddi-
tions: Fillion, H.; Luche, J .-L. In Synthetic Organic Sonochemistry;
Luche, J .-L., Ed.; Plenum Press: New York, 1998; pp 91-106 and
references therein.
(10) Reactions were run in
a monomode reactor with focused
electromagnetic radiation (see Experimental Section). This enables a
homogeneous distribution of the electric field and consequently an
almost complete reproducibility of experiments. Similar results can
also be obtained with a domestic oven operating at the same frequency,
but the reproducibility is often poorer.
(11) Sommer, S.; Schubert, U. Angew. Chem., Int. Ed. Engl. 1979,
18, 696-697.
(6) Avalos, M.; Babiano, R.; Cintas, P.; J ime´nez, J . L.; Palacios, J .
C.; Sa´nchez, J . B. Tetrahedron: Asymmetry 1995, 6, 945-956. This
optimized protocol involves a two-step sequence from commercially
available unprotected sugars.
(12) (a) Boger, D. L.; Coleman, R. S. J . Org. Chem. 1984, 49, 2240-
2245. (b) Boger, D. L.; Sakya, S. M. J . Org. Chem. 1988, 53, 1415-
1423. (c) Boger, D. L.; Schaum, R. P.; Garbaccio, R. M. J . Org. Chem.
1998, 63, 6329-6337 and references therein.

Hetero-Diels-Alder Reactions under Microwave Irradiation
J . Org. Chem., Vol. 64, No. 17, 1999 6299
Sch em e 1
Sch em e 2
deshielded signal appears at ∼7 ppm as a doublet, which
can be attributed to H-5, the azomethine proton. Also 13
C
NMR spectra were used to confirm such structures: the
chemical shifts of C-1′ to C-4′ carbon signals are consis-
tent with typical values found for acyclic carbohydrate
skeleta,15 and the resonance at ∼135 ppm is character-
istic of the azomethine carbon16 at C-5.
Furthermore, these tetrazines were analyzed by mass
spectrometry and three different fragmentation patterns
were observed: (a) the loss of a CO2Et moiety followed
by sequential elimination of acetic acid and acetate units,
(b) the elimination of ketene (CH2CO) and acetate units,
and (c) the initial elimination of an ArN2 fragment
followed by the loss of acetate and acetic acid as key
fragments. These results provided clear information on
the overall sugar and heterocycle compositions. For
compound 8, the presence of the above series of fragment
ions at m/z 570 and 568 [M - AcOH]•+, 557 and 555 [M
- CO2Et]•+, and 489 [M - ArN2]•+ accompanied by
abundant ions at m/z 141 and 139 [ArN2]•+, 73, 60, and
43 gave positive evidence for the formation of cycload-
ducts.
Ta ble 1. Nor m a l Electr on Dem a n d Aza -Diels-Ald er
Rea ction s of Ca r boh yd r a te-Ba sed
1-Ar yl-1,2-d ia za -1,3-bu ta d ien es (1-6) w ith DEAD
Con figu r a tion a l Assign m en t a n d Ster ic Cou r se.
Having demonstrated by X-ray diffractometry that the
major diastereomers display (6R)-configurations if the
chiral descriptor of the heterodiene at C-1′ (the first
stereogenic center of the sugar chain) is R (e.g., 1-5),
we see that the relative induction arises from the
preferential reaction of DEAD with the Re face of the
azoalkene (Scheme 2). This results in a like (lk) combina-
tion,17 and the stereochemical course can be designated
in a self-consistent fashion as [R(1)ReR(4)Re].18
diastereoemeric
ratioa
yield
(%)b
heterodiene
cycloadducts
1
2
3
4
5
6
7 + 11
8 + 12
9 + 13
10 + 14
15 + 16
17 + 18
85:15
84:16
88:12
85:15
66:33
35:65
93
96
87
92
91
80
Determined by 1H NMR peak integration in CDCl3 solution.
Combined yields of (6R)- and (6S)-diastereomers.
a
b
These assumptions fully agree with the experimental
results. Thus compound 12, epimer of 8 at C-6, should
have the opposite configuration at that stereogenic
carbon. Furthermore, the circular dichroism (CD) spectra
of 8 and 12 are approximately mirror images (Figure 1).
This does mean that the sign of the CD and its ellipticity
will largely be dependent on the absolute configuration
at C-6, with little or no influence provided by the
remaining stereocenters of the polyacetylated chain.
Since the CD spectrum of 17 is analogous to that of 8,
such substances should have the same configuration (R)
at C-6. In stark contrast, the CD spectra of 12 and 18
exhibit opposite signs over the entire wavelength range,
consistent with their (6S)-configuration (Figure 2).
The above data are also corroborated by the values of
optical rotation. This fact has allowed us to establish a
useful empirical correlation between the sign of the
fashion (see Experimetal Section). In addition, the solid-
state structure of 8 could be unequivocally determined
by single-crystal X-ray diffractometry.13 The X-ray in-
vestigation was carried out to elucidate the configuration
of the new stereogenic center at C-6.14 The results of the
crystal structure determination indicate that the new
chiral center is R, a fact that can be harnessed to
rationalize the steric course (vide infra). It should also
be noted that the tetrahydrotetrazine ring exhibits a
conformation near to a half-boat, with a dihedral angle
between the heterocycle mean plane and the aromatic
ring of 153.2°, and that between the tetrahydrotetrazine
mean plane and the sugar chain plane of 71.3°.13
Double irradiation experiments were used to assign the
remaining protons in the 1H NMR spectra of adducts. The
two diethyl groups resonate at different chemical shifts,
thereby evidencing the different environment surround-
ing both carboxylates in the heterocyclic ring. The most
(15) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem. 1983,
41, 27-66.
(16) Pretsch, E.; Clerc, T.; Seibl, J .; Simon, W. Tablas para la
Elucidacio´n Estructural de Compuestos Orga´nicos por Me´todos Espe-
ctrosco´picos; Alhambra: Madrid, 1980; p 89.
(17) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982, 21,
654-660.
(18) Avalos, M.; Babiano, R.; Cintas, P.; J ime´nez, J . L.; Palacios, J .
C. Tetrahedron: Asymmetry 1996, 7, 2333-2342.
(13) Dia´nez, M. J .; Estrada, M. D.; Lo´pez-Castro, A.; Pe´rez-Garrido,
S. Acta Crystallogr. 1994, C50, 1972-1974.
(14) For compound 8 we had assigned5a the absolute configuration
S by comparison of its circular dichroism spectrum with that of a model
compound: Ogura, H.; Sakaguchi, M.; Nakata, K.; Hida, N.; Takeuchi,
H. Chem. Pharm. Bull. 1981, 29, 629-634.

6300 J . Org. Chem., Vol. 64, No. 17, 1999
Avalos et al.
rotation of 8 would be the sum of C-6 (R) and acyclic
chain (C) contributions to the rotatory power:
[R]D ) +382° ) R + C
(1)
and analogously, it is possible to establish a relationship
for its epimer 12 (since R ) -S):
[R]D ) -174° ) S + C ) -R + C
(2)
The subtraction of both equations gives the contribu-
tion of C-6(R):
+556° ) 2R w R ) +278°
Likewise, the addition of (1) and (2) gives the chain
contribution:
F igu r e 1. Circular dichroism spectra of 8 and 12 (dotted line)
recorded in EtOH.
+208° ) 2C w C ) +104°
Since the magnitude of C-6(R) is greater than that of
C, the absolute configuration at C-6 will be determined
by the sign of the optical rotation, a surmise in agreement
with experimental data from Table 2. An analogous
reasoning can be applied to other epimeric pairs such as
15/16 (R ) +205°, C ) +6°) and 17/18 (R ) +193°, C )
+24°). Consequently, in the case of adducts arising from
a cycloaddition of 1,2-diazoalkenes with DEAD, a positive
value of the optical rotation indicates R-configuration at
C-6, whereas a negative value agrees with S-configura-
tions.
Conventional wisdom has held that the nearest ste-
reocenter to a reacting moiety greatly influences the
asymmetric induction. This is de facto an indirect con-
firmation of the principle of optical superposition, which
has also been observed, for instance, by Franck and co-
workers in the facial diastereoselectivity of Diels-Alder
reactions with chiral 1,3-butadienes.22 Table 1 provides
an outstanding confirmation of this principle: starting
from 6, whose absolute configuration at C-1′ is S, the
major stereoisomer (18) has now (6S)-configuration. An
additional striking point, already mentioned, is the fact
that the diastereomeric ratio is also dependent on the
configuration of the second stereocenter. A threo vicinal
relationship causes a higher level of diastereoselection
than the corresponding erythro arrangement. Even though
the latter rule should be applied with caution, we have
found that this structural feature has a predictive value
on acyclic stereoselection.23
F igu r e 2. Circular dichroism spectra of diastereomers 17 and
18 (dotted line) in EtOH solution.
Ta ble 2. Con figu r a tion (C-6) a n d Op tica l Rota tion of
Ad d u cts 7-12 a n d 15-18
configuration
cycloadduct
(C-6)a
[R]D (deg)b
7
8
R
R
R
R
S
+333.5
+381.5
+422.3
+417
9
10
11
12
15
16
17
18
-165.6
-174
S
R
S
R
S
+414
-403.2
+408
Rea ction of 1,2-Dia zoa lk en es w ith DEAD. A Th eo-
r etica l Stu d y. A systematic molecular orbital (MO)
calculation appeared to be essential in order to rationalize
the results obtained in the above-mentioned experimental
studies of 1,2-diaza-1,3-butadienes. The importance of
this study is 2-fold. Unlike monoaza-1,3-butadienes which
-361
a
b
By X-ray analysis and empirical correlation (see text). See
Experimental Section for details.
optical rotation and the configuration of adducts. Table
2 depicts the magnitude and sign of the optical rotation
along with the configuration at C-6 as previously estab-
lished.
From these data, it can be seen that adducts 7 and 11
exhibit large optical rotations but with opposite configu-
rations. Applying van’t Hoff’s principle of optical super-
position19,20 and using an analysis similar to that of
Hudson’s rules,21 it is possible to calculate the contribu-
tion of C-6 to the rotatory power. Thus, the optical
(20) The principle of optical superposition states that individual
chiral centers in a chiral compound make independent contributions
to the molar rotation. Although it ignores solvent and concentration
effects, its application has proven to be successful in many instances.
Sometimes the existence of vicinal stereocenters renders the principle
invalid (see ref 19).
(21) (a) Hudson, C. S. J . Am. Chem. Soc. 1909, 31, 66-86. (b)
Hudson, C. S. J . Am. Chem. Soc. 1916, 38, 1566-1575. (c) Ferrier, R.
J . In The Carbohydrates. Chemistry and Biochemistry; Pigman, W.,
Horton, D., Wander, J . D., Eds.; Academic Press: New York, 1980;
Vol. IB, pp 1356-1362.
(22) Tripathy, R.; Franck, R. W.; Onan, K. D. J . Am. Chem. Soc.
1988, 110, 3257-3262.
(23) Avalos, M.; Babiano, R.; Cintas, P.; J ime´nez, J . L.; Palacios, J .
C. Unpublished results.
(19) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 1081-1082 and
references therein.

Hetero-Diels-Alder Reactions under Microwave Irradiation
Ta ble 3. En th a lp ies (∆Hf, k ca l/m ol), Bon d Len gth s (Å), a n d Dih ed r a l An gles (d eg) for Cycloa d d u cts a n d TSs 20-23
cycloadducts (PM3) transition structures (PM3)
J . Org. Chem., Vol. 64, No. 17, 1999 6301
20
21
22
23
TS20
TS21
TS22
TS23
∆Hf
-145.72
1.511
1.525
130.20
-145.58
1.517
1.488
127.36
-142.54
1.506
1.529
131.83
-147.29
1.514
1.492
128.19
-105.61
2.054
1.845
152.54
-97.71
2.026
1.887
152.10
-98.40
2.056
1.847
152.79
-98.10
2.019
1.889
152.99
N1-C6
N2-N3
CO-N1-N2-CO
have been the subject of numerous theoretical studies at
semiempirical and ab initio levels,24 1,2-diazadienes
remain a rather unexplored domain.25 On the other hand,
it is necessary to check the precise effect of the chiral
framework on the facial selectivity.
side chain, the same relative configuration found in the
two stereogenic carbons (C-1′ and C-2′) of the protected
heterodienes 1-4.
Previous studies on the TSs of 2-aza-1,3-butadienes
involved in Diels-Alder reactions24d,e reveal that the
presence of a nitrogen atom in the diene enhances the
electrophilicity and lowers the energy of the MOs, thereby
making the heterodiene less reactive than 1,3-butadiene
toward electron-withdrawing dienophiles. Inverse Diels-
Alder reactions with electron-rich dienophiles are favored
by substituting the azadiene with electron-withdrawing
groups, which makes the latter still more electron-
deficient. In contrast, normal electron demand reactions
occur when the azadiene is substituted with electron-
donating groups. It is also interesting to note that the
HOMO of 2-azadiene is slightly polarized, although the
effect of the nitrogen substitution on the LUMO is more
pronounced with the C-1 coefficient larger than that of
C-4. Anyhow, the regioselectivity displayed by substi-
tuted 2-aza-1,3-butadienes is similar to that of a substi-
tuted 1,3-butadiene.24e
When dealing with computational methods, the most
important question is to ascertain whether a reduced
model can reproduce accurately the behavior of the
experimental systems, which do not react generally in
the gas phase. Accordingly, we have undertaken different
studies to evaluate the influence of a chiral substituent
at C-4 with a relative threo configuration, the presence
of an aromatic ring at N-1 of the 1,2-diazadiene, the
configuration and substituents of the heterodienophile,
and its possible endo/exo approaches.
The frontier orbital calculations (FMO)28 of diazadiene
19 and DEAD determined by PM3 calculations predict
the tendency to react in a normal HOMOdiene-controlled
Diels-Alder reaction because the energy gap HOMOdiene
- LUMOdienophile (∆E ) 8.78 eV) is lower than the energy
of the interaction HOMOdienophile - LUMOdiene (∆E ) 9.46
eV). For the fact that neither the Hij differential overlap
integrals or steric effects are included in the FMO
analysis, the TSs for the reactions of 19 were calculated.
Assuming that DEAD maintains its (E)-configuration
during the Diels-Alder reaction, there are four possible
TSs (20-23) concerning the approaches to both Re and
Si faces of the heterodiene 19. Nevertheless, the rapid
configurational inversion of the chiral nitrogen atoms in
the heterocyclic ring results in cycloadducts that only
differ by (R)- or (S)-configuration at C-6 (Scheme 3).
Table 3 depicts the most significant parameters cal-
culated from PM3-optimized geometries of the TSs and
the corresponding cycloadducts (Figures 3 and 4).
It is noteworthy the greater stability of the TS 20
which accounts for the preferential formation of adduct
20 having (6R)-configuration. This result agrees with the
experimental observation favoring (6R)-configurated cy-
cloadducts such as 7-10. The diastereoselective forma-
tion of these products can be rationalized to result from
steric interactions, since the Re face of the heterodiene
is readily accessible while the approach to the Si face is
impeded by the chiral substituent at C-4 of the hetero-
diene. However, the distances of the forming bonds (N1-
C6 and N2-N3) as well as the torsional angle of DEAD
display similar features. Globally, in these studies the
N1-C6 distance differs by <0.01 Å in cycloadducts and
Owing to the increasing molecular size of these models,
which include numerous heteroatoms, ab initio MO
calculations could not be performed at a reasonable
computational cost. Alternatively, semiempirical calcula-
tions at PM3 level,26 one of the most robust methods,
were carried out involving full optimizations using the
Gaussian 94 series of programs.27 Preliminary examina-
tion of these data reveal that calculations closely match
the experimental results.
We first examined the reacting system consisting of
1,2-diaza-1,3-butadiene 19 plus DEAD. This is very close
to the real situation. Compound 19 possesses a D-threo
(24) (a) Nomura, Y.; Takeuchi, Y.; Tomoda, S.; Ito, M. M. Bull. Chem.
Soc. J pn. 1981, 54, 2779-2785. (b) Boger, D. L.; Corbett, W. L.; Curran,
T. T.; Kasper, A. M. J . Am. Chem. Soc. 1991, 113, 1713-1729. (c)
Bachrach, S. M.; Liu, M. J . Am. Chem. Soc. 1991, 113, 7929-7937.
(d) Bachrach, S. M.; Liu, M. J . Org. Chem. 1992, 57, 6736-6744. (e)
Gonza´lez, J .; Houk, K. N. J . Org. Chem. 1992, 57, 3031-3037. (f) Sisti,
N. J .; Motorina, I. A.; Tran Huu Dau, M.-E.; Riche, C.; Fowler, F. W.;
Grierson, D. S. J . Org. Chem. 1996, 61, 3715-3728. (g) Pinho e Melo,
T. M. V. D.; Fausto, R.; Rocha Gonsalves, A. M. A.; Gilchrist, T. L. J .
Org. Chem. 1998, 63, 5350-5355. (h) Augusti, R.; Gozzo, F. C.; Moraes,
L. A. B.; Sparrapan, R.; Eberlin, M. N. J . Org. Chem. 1998, 63, 4889-
4897.
(27) (a) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. M.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian
94, Revision D.1; Gaussian, Inc.: Pittsburgh, PA, 1995. (b) Frisch, M.
J .; Frisch, Æ.; Foresman, J . B. Gaussian 94 User’s Reference; Gaussian,
Inc.: Pittsburgh, PA, 1994-1996.
(28) (a) Dewar, M. J . S. Molecular Orbital Theory for Organic
Chemists; McGraw-Hill: New York, 1969. (b) Fleming, I. Frontier
Orbitals and Organic Chemical Reactions; Wiley: New York, 1976;
Chapter 2, pp 5-32.
(25) For instance: Orsini, F.; Sala, G. Tetrahedron 1989, 45, 6531-
6536.
(26) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220.

6302 J . Org. Chem., Vol. 64, No. 17, 1999
Avalos et al.
Ta ble 4. Hea ts of F or m a tion (∆Hf, k ca l/m ol),
Ch a r a cter istic Bon d Len gth s (Å), a n d Tor sion An gles
Sch em e 3
(d eg) for th e TSs a n d Cycloa d d u cts of 24 + DEAD
cycloadducts
(PM3)
transition structures
(PM3)
25
26
TS25
TS26
∆Hf
-57.21
1.510
1.525
129.99
-56.04
1.516
1.490
128.94
-16.60
2.064
1.844
152.92
-8.58
2.030
1.887
N1-C6
N2-N3
CO-N1-N2-CO
151.64
Ta ble 5. Ch a r ge Distr ibu tion on Atom s for th e TSs of
Diels-Ald er Rea ction s
heterodiene
heterodienophile
q(N2)
q(C3)
q(CdO)
TS20
TS21
TS25
TS26
TS28
TS29
-0.02
-0.04
-0.02
-0.03
-0.06
-0.06
-0.27
-0.23
-0.31
-0.27
-0.26
-0.26
+0.44
+0.42
+0.44
+0.42
+0.44
+0.41
kcal/mol). Such a difference is similar to the energy gap
between the TS 20 and TS 21 (vide supra) and accounts
for the preferential formation of 25 involving an endo
approach of DEAD to C-4 and an exo attack to N-1 of the
heterodiene. Unfortunately, a clear-cut explanation for
the selective orientation of DEAD (e.g., its facial selection)
during its approach to the heterodiene does not issue
from the above data. Perhaps, the existence of either an
aromatic substituent at N-1 of the heterodiene or an
aliphatic one at C-4 also dictates the stereochemical
outcome. For this reason, we performed a calculation for
the prototype Diels-Alder reaction of 1,2-diazabutadiene
27 plus DEAD leading to 28 and 29 (Scheme 5). The
energy gap between both TSs (∆E ) 6.67 kcal/mol) was
similar to those found between 25 and 26, and 20 and
21. A similar result (∆E ) 6.24 kcal/mol) was also
encountered for the reaction of 27 and HNdNH.
These results rule out the influence of substituents,
at least critically, on the steric course. On the other hand,
the energy differences >6 kcal/mol cannot be rationalized
to result from weak secondary orbital interactions. To
have a partial appreciation of the electronic component
which contributes, or likely controls, the regiochemistry
of the Diels-Alder reaction, the charge distributions were
examined. Mulliken population analysis shows that in
all cases the charge distribution on the individual atoms
N-2 and C-3 of the heterodiene have a negative value
(q < 0). In stark contrast the carbon atom of the
carboxylate group lying on the endo orientation with
respect to the heterodiene has a positive value (Table 5).
For each TS, the atoms superposed in the approach of
both reaction partners are underlined. The electrostatic
interaction is significant for the TSs 20, 25, and 28, which
are model structures for the formation of the (6R)-
configurated adducts 7-10.
by no more than 0.04 Å in TSs. The other distance N2-
N3 differs by less than 0.05 Å. The cycloadditions are all
asynchronous by virtue of the distinctive nature of bonds
involved, but they also exhibit a high degree of concert-
edness.
To evaluate the influence of the acyclic side chain, we
did study a reduced model (24) in which the threo-
configured substituent was replaced by a methyl group,
but preserving the characteristic (E,E)-configuration of
1,2-diazabutadienes.
Con clu sion s
The absence of stereogenic centers in 24 now renders
both approaches enantiotopic, a fact that also reduces the
diastereomeric possibilites by half, both of them inter-
convertible by configurational inversion of nitrogen atoms
N-1 and N-2 (Scheme 4, Table 4).
Again, the energy for the TS 25 is lowered to a much
greater extent than the energy for the TS 26 (∆E ) 8.02
The normal aza-Diels-Alder reactions of optically
active 1,2-diaza-1,3-butadienes derived from carbohy-
drates (1-6) react with DEAD to afford a diastereomeric
mixture of (6R)- and (6S)-configured 1,2,3,6-tetrahydro-
1,2,3,4-tetrazines (7-18) in good yields. Diastereomeric
ratios of ∼85:15 are obtained from heterodienes having

Hetero-Diels-Alder Reactions under Microwave Irradiation
J . Org. Chem., Vol. 64, No. 17, 1999 6303
F igu r e 3. PM3-optimized geometries of the cycloadducts 20-23 generated by face-selective reactions of 19 and DEAD. For
clarity, hydrogen atoms have been omitted.
Sch em e 4
monitored by TLC on silica gel 60 F254; the positions of the
spots were detected with 254-nm UV light and with iodine
vapors. Flash chromatography29 was performed on columns
of silica gel (400-230 mesh) using ether-hexane (1:1, v/v) as
eluent. Optical rotations were measured on a polarimeter at
25 °C in the stated solvent. 1H and 13C NMR spectra were
recorded at 20 °C in CDCl3 on spectrometers operating at 400
or 200 MHz and at 100 or 50.3 MHz, respectively. Chemical
shifts are expressed in ppm positive values downfield from
internal TMS and apparent coupling constants are given in
hertz. Circular dichroism spectra were recorded on a automatic
spectropolarimeter; the concentrations of the CD samples were
ascertained from the UV spectra. High-resolution mass spectra
(HRMS/EI) were obtained at 70 eV with an ionizing current
of 100 µA and accelerating voltage of 4 kV. Elemental analyses
were performed by the Servei de Microana`lisi del CSIC,
Barcelona.
threo configuration at C-1′,2′ of the side chain, whereas
a lower stereoselection is obtained from a relative erythro
configuration. The reactions are impractical at room
temperature, but are completed within a few hours under
microwave heating with the same sense and level of
stereoselection. A careful inspection of the optical rota-
tions of cycloadducts enables anticipation of a useful
correlation between the rotatory power and the absolute
configuration of tetrazines at C-6. The approach of DEAD
to the Re face of the heterodiene occurs if the first chiral
center of the sugar chain is R and results in (6R)-
configured cycloadducts. To rationalize the experimental
results, theoretical calculations on the reactants, prod-
ucts, and transition structures were performed at a
semiempirical level, which we have been forced to employ
because of the complexity of the system under study. This
exploration reveals that the steric course is not critically
affected by the nature of substituents, and a better
stabilization is due to the electrostatic interaction during
the approach of both reactants.
Micr ow a ve-Assisted Syn th eses. Reactions were run in
a reactor of focused microwaves with a magnetron operating
at a frequency at 2.45 GHz and a maximum power output of
300 W. The quartz flask, protected with a polyurethane coating
and by a quartz glove finger, is heated in a closed cavity located
inside the instrument with continuous stirring. The temper-
ature is measured by an IR pyrometer in the range from 0 to
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
capillary apparatus and are uncorrected. Reactions were
(29) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

6304 J . Org. Chem., Vol. 64, No. 17, 1999
Avalos et al.
F igu r e 4. PM3-optimized geometries of TSs 20-23. For the sake of clarity, hydrogen atoms have been omitted.
Sch em e 5
450 °C. The microwave module is driven by computer which
controls temperature curves and power setpoints (between 0
and 100%).
mmol), and the reaction mixture was kept at room tempera-
ture. TLC monitoring (ether-hexane, 2:1) revealed, after 24
h, the formation of two yellow spots with approximate Rf
values of 0.5 (compounds 7-10, 15, 17) and 0.4 (compounds
11-14, 16, 18). After 30 days, the solvent was removed under
vacuum, and the residue was flash column chromatographed.
Gen er a l P r oced u r es for th e P r ep a r a tion of 6-(1′,2′,3′,4′-
Te t r a -O-a ce t yl-D-a r a bin o-t e t r it ol-1′-yl)-3-a r yl-1,2-b is-
(et h oxyca r b on yl)-1,2,3,6-t et r a h yd r o-1,2,3,4-t et r a zin es
(7-12). Meth od A: To a solution of the corresponding (1E,3E)-
4-(1′,2′,3′,4′-tetra-O-acetyl-D-arabino-tetritol-1′-yl)-1-aryl-1,2-
diaza-1,3-butadiene (1-4) (4.60 mmol) in dry benzene (35 mL)
was added diethyl azodicarboxylate (DEAD) (3.6 mL, 21.72
Meth od B: A suspension of the corresponding 1,2-diaza-
1,3-butadiene (1-4) (1.0 mmol) in neat DEAD (0.4 mL, 2.5
mmol) was subjected to microwave irradiation (300 W, 5%).
TLC monitoring (ether-hexane, 2:1) revealed, after 15 min,

Hetero-Diels-Alder Reactions under Microwave Irradiation
J . Org. Chem., Vol. 64, No. 17, 1999 6305
the appearance of two yellow spots with Rf values of ∼0.5 and
∼0.4. After 6 h the solvent was evaporated, and cycloadducts
were isolated as described above.
1H), 5.50 (dd, J ) 10.3 Hz, 1.6 Hz, 1H), 5.23 (ddd, J ) 8.3 Hz,
6.6 Hz, 2.9 Hz, 1H), 4.85 (dd, J ) 10.3 Hz, 3.5 Hz, 1H), 4.36-
4.22 (m, 3H), 4.13-3.95 (m, 3H), 3.73 (s, 3H), 2.13 (s, 6H), 2.01
(s, 6H), 1.36 (t, J ) 7.1 Hz, 3H), 1.02 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 169.8, 169.2, 169.2, 155.5, 154.4, 138.4, 136.0,
127.7, 117.4, 113.2, 68.3, 67.7, 67.0, 63.8, 62.9, 61.9, 54.7, 50.4,
20.1, 20.0, 19.8, 19.8, 13.6, 13.3; HRMS found 624.2273
(C27H36N4O13 requires 624.2279), ∆ ) 0.9 ppm.
(6R)- a n d (6S)-6-(1′,2′,3′,4′-Tetr a -O-a cetyl-D-a r a bin o-
t et r it ol-1′-yl)-1,2-b is(et h oxyca r b on yl)-3-p h en yl-1,2,3,6-
tetr a h yd r o-1,2,3,4-tetr a zin es (7 a n d 11). These substances
were obtained as yellowish oils in 93% overall yield. The
diastereomeric ratio (85:15) was determined by 1H NMR
integration of the residue. Compound 7 had [R]D +333.5° (c
0.5, CHCl3); 1H NMR (CDCl3) δ 7.27 (m, 5H), 6.92 (d, J ) 3.5
Hz, 1H), 5.64 (dd, J ) 8.1 Hz, 1.7 Hz, 1H), 5.52 (dd, J ) 10.2
Hz, 1.7 Hz, 1H), 5.23 (m, 1H), 4.83 (dd, J ) 10.2 Hz, 3.5 Hz,
1H), 4.38-4.02 (m, 6H), 2.16 (s, 6H), 2.05 (s, 6H), 1.26 (t, J )
7.1 Hz, 3H), 1.09 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 170.4,
169.7, 169.7, 169.6, 154.8, 144.4, 135.1, 128.5, 122.4, 115.0,
69.0, 68.3, 67.5, 64.4, 63.6, 62.4, 51.1, 20.7, 20.6, 20.5, 20.4,
14.0, 13.8; HRMS found 594.2147 (C26H34N4O12 requires
594.2173), ∆ ) 4.3 ppm. Compound 11: [R]D -165.6° (c 0.5,
(6R)- a n d (6S)-6-(1′,2′,3′,4′-Tetr a -O-a cetyl-D-lyxo-tetr i-
tol-1′-yl)-1,2-bis(eth oxycar bon yl)-3-ph en yl-1,2,3,6-tetr ah y-
d r o-1,2,3,4-tetr a zin es (15 a n d 16). These diastereomers
were isolated in 91% overall yield (dr ) 66:33). Compound
15: crystals from benzene, mp 140 °C, [R]D +414° (c 0.5,
1
CHCl3); H NMR (CDCl3) δ 7.29 (m, 4H), 7.17 (d, J ) 3.5 Hz,
1H), 7.00 (m, 1H), 5.58 (t, J ) 4.6 Hz, 1H), 5.47 (m, 1H), 5.36
(dd, J ) 4.1 Hz, 3.1 Hz, 1H), 4.98 (t, J ) 3.1 Hz, 1H), 4.31 (dd,
J ) 12.0 Hz, 4.7 Hz, 1H), 4.24-4.10 (m, 5H), 2.16 (s, 3H), 2.11
(s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.24 (t, J ) 7.1 Hz, 3H), 1.18
(t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 170.3, 169.9, 169.4,
169.2, 154.3, 154.0, 144.6, 136.4, 128.6, 122.5, 114.9, 72.9, 69.8,
68.6, 64.1, 63.4, 61.6, 52.5, 20.7, 20.6, 20.5, 14.0, 14.0. Anal.
Calcd for C26H34N4O12: C, 52.51; H, 5.76; N, 9.42. Found: C,
52.51; H, 5.90; N, 9.49.
1
CHCl3); H NMR (CDCl3) δ 7.30 (m, 5H), 7.01 (d, J ) 3.0 Hz,
1H), 5.75 (dd, J ) 6.5 Hz, 5.1 Hz, 1H), 5.48 (dd, J ) 6.5 Hz,
4.6 Hz, 1H), 5.36 (m, 1H), 4.99 (dd, J ) 4.6 Hz, 3.0 Hz, 1H),
4.44 (dd, J ) 11.5 Hz, 3.7 Hz, 1 H), 4.35-4.10 (m, 5H), 2.10
(s, 6H), 2.07 (s, 6H), 1.26 (t, J ) 7.0 Hz, 3H), 1.16 (t, J ) 7.0
Hz, 3H); 13C NMR (CDCl3) δ 170.4, 169.6, 169.4, 155.5, 153.5,
145.0, 134.1, 128.6, 122.5, 115.0, 70.0, 69.2, 63.9, 63.7, 61.3,
53.1, 20.6, 20.5, 14.2, 14.0.
Compound 16: [R]D -403.2° (c 0.5, CHCl3); 1H NMR (CDCl3)
δ 7.31-7.21 (m, 4H), 7.02-6.94 (m, 1H), 6.91 (d, J ) 3.7 Hz,
1H), 5.74 (bs, 1H), 5.52 (dd, J ) 10.2 Hz, 2.8 Hz, 1H), 5.35
(ddd, J ) 8.1 Hz, 4.0 Hz, 1.5 Hz, 1H), 4.95 (t, J ) 3.4 Hz, 1H),
4.40 (dd, J ) 11.8 Hz, 4.0 Hz, 1H), 4.37 (bs, 2H), 4.13-3.95
(m, 2H), 3.81 (bs, 1H), 2.16 (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H),
1.99 (s, 3H), 1.46 (bs, 3H), 1.08 (t, J ) 7.1 Hz, 3H); 13C NMR
(CDCl3) δ 170.3, 170.2, 169.7, 169.4, 155.6, 153.5, 144.6, 134.3,
128.6, 122.4, 115.0, 68.1, 68.0, 67.6, 63.8, 63.7, 62.9, 52.6, 20.8,
20.6, 20.5, 14.2, 13.8.
(6R)- a n d (6S)-6-(1′,2′,3′-Tr i-O-a cetyl-D-er yth r o-tr itol-1′-
yl)-3-(4-b r om op h en yl)-1,2-b is(et h oxyca r b on yl)-1,2,3,6-
tetr a h yd r o-1,2,3,4-tetr a zin es (17 a n d 18). Diastereomers
were isolated in 80% overall yield (dr ) 35:65). Compound
17: Crystals from ether-hexane, mp 132 °C, [R]D +408° (c
0.5, CHCl3); 1H NMR (CDCl3) δ 7.37 (d, J ) 9.0 Hz, 2H), 7.13
(d, J ) 9.0 Hz, 2H), 6.94 (d, J ) 3.6 Hz, 1H), 5.59 (dd, J )
10.1 Hz, 2.6 Hz, 1H), 5.51 (m, 1H), 4.99 (dd, J ) 3.6 Hz, 2.6
Hz, 1H), 4.50-4.20 (m, 4H), 4.18-4.01 (m, 2H), 2.12 (s, 3H),
2.05 (s, 3H), 2.01 (s, 3H), 1.37 (t, J ) 7.0 Hz, 3H), 1.14 (t, J )
7.1 Hz, 3H); 13C NMR (CDCl3) δ 170.2, 169.4, 168.9, 155.0,
153.1, 143.4, 135.0, 131.3, 116.2, 114.6, 68.2, 67.5, 63.7, 63.6,
(6R)- a n d (6S)-6-(1′,2′,3′,4′-Tetr a -O-a cetyl-D-a r a bin o-
tetr itol-1′-yl)-3-(4-ch lor op h en yl)-1,2-bis(eth oxyca r bon yl)-
1,2,3,6-tetr a h yd r o-1,2,3,4-tetr a zin es (8 a n d 12). These
diastereomers were obtained in 96% overall yield (dr ) 84:
16). Compound 8 was crystallized from ether and had mp 112
1
°C, [R]D +381.5° (c 0.5, CHCl3); H NMR (CDCl3) δ 7.22 (m,
4H), 6.90 (d, J ) 3.5 Hz, 1H), 5.63 (dd, J ) 8.2 Hz, 1.9 Hz,
1H), 5.50 (dd, J ) 10.1 Hz, 1.9 Hz, 1H), 5.23 (ddd, J ) 8.2 Hz,
6.6 Hz, 2.9 Hz, 1H), 4.82 (dd, J ) 10.1 Hz, 3.5 Hz, 1H), 4.43-
4.23 (m, 3H), 4.15-4.01 (m, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 2.05
(s, 6H), 1.33 (t, J ) 7.1 Hz, 3H), 1.13 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 170.5, 169.8, 169.7, 169.7, 154.8, 154.7, 143.1,
135.5, 128.6, 127.5, 116.1, 69.0, 68.3, 67.6, 64.7, 63.9, 62.5, 51.2,
20.8, 20.7, 20.7, 20.6, 14.1, 14.0; HRMS found 628.1781 (C26H33
ClN4O12 requires 628.1783), ∆ ) 0.4 ppm. Anal. Calcd for
26H33ClN4O12: C, 49.65; H, 5.24; N, 8.90. Found: C, 49.58;
-
C
H, 5.22; N, 8.83.
Compound 12: yellow oil, [R]D -174° (c 0.5, CHCl3); 1H NMR
(CDCl3) δ 7.22 (m, 4H), 7.00 (d, J ) 3.2 Hz, 1H), 5.74 (dd, J )
6.4 Hz, 4.9 Hz, 1H), 5.48 (dd, J ) 6.4 Hz, 4.5 Hz, 1H), 5.36 (m,
1H), 4.99 (m, 1H), 4.48-4.07 (m, 6H), 2.11 (s, 3H), 2.09 (s, 3H),
2.04 (s, 3H), 2.03 (s, 3H), 1.38-1.13 (m, 6H); 13C NMR (CDCl3)
δ 170.5, 169.6, 169.4, 169.4, 155.4, 153.3, 143.1, 134.4, 128.6,
127.5, 116.1, 70.1, 70.0, 69.3, 64.1, 63.9, 61.3, 53.1, 20.7, 20.6,
20.5, 14.2, 14.0.
61.0, 52.7, 20.7, 20.3, 14.0, 13.8; HRMS found 600.1063 (C23H29
BrN4O10 requires 600.1067), ∆ ) 0.8 ppm. Anal. Calcd for
23H29BrN4O10: C, 45.93; H, 4.91; N, 9.32. Found: C, 45.93;
-
C
H, 4.92; N, 9.24.
Compound 18: [R]D -361° (c 0.5, CHCl3); 1H NMR (CDCl3)
δ 7.39 (d, J ) 9.0 Hz, 2H), 7.18 (d, J ) 9.0 Hz, 2H), 7.15 (d, J
) 3.4 Hz, 1H), 5.49 (dt, J ) 6.1 Hz, 3.9 Hz, 1H), 5.38 (t, J )
3.9 Hz, 1H), 4.94 (dd, J ) 3.9 Hz, 3.4 Hz, 1H), 4.45 (dd, J )
12.2 Hz, 3.9 Hz, 1H), 4.33 (dd, J ) 12.2 Hz, 6.1 Hz, 1H), 4.28-
4.13 (m, 4H), 2.13 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 1.35-1.19
(m, 6H); 13C NMR (CDCl3) δ 170.0, 169.2, 169.0, 154.0, 153.7,
143.5, 136.5, 131.3, 116.1, 114.6, 72.8, 69.9, 64.2, 63.3, 61.4,
52.1, 20.5, 20.3, 13.9, 13.8.
(6R)-6-(1′,2′,3′,4′-Tet r a -O-a cet yl-D-a r a bin o-t et r it ol-1′-
yl)-1,2-b is(et h oxyca r b on yl)-3-(4-m et h ylp h en yl)-1,2,3,6-
tetr a h yd r o-1,2,3,4-tetr a zin e (9). This compound was iso-
1
lated as an oil in 87% yield: [R]D +422.3° (c 0.5, CHCl3); H
NMR (CDCl3) δ 7.16 (d, J ) 8.6 Hz, 2H), 7.07 (d, J ) 8.6 Hz,
2H), 6.91 (d, J ) 3.6 Hz, 1H), 5.63 (dd, J ) 8.2 Hz, 1.7 Hz,
1H), 5.50 (dd, J ) 10.2 Hz, 1.7 Hz, 1H), 5.23 (ddd, J ) 8.2 Hz,
6.7 Hz, 2.9 Hz, 1H), 4.85 (dd, J ) 10.2 Hz, 3.6 Hz, 1H), 4.40-
4.00 (m, 6H), 2.29 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 2.04 (s,
6H), 1.34 (t, J ) 7.1 Hz, 3H), 1.08 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 170.4, 169.7, 169.7, 169.6, 154.8, 142.4, 135.0,
132.0, 129.0, 115.4, 68.9, 68.3, 67.5, 64.4, 63.5, 62.4, 51.0, 20.8,
20.7, 20.6, 20.5, 20.4, 14.1, 13.8; HRMS found 608.2330
(C27H36N4O12 requires 608.2329), ∆ ) 0.2 ppm.
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the Direccio´n General de Investi-
gacio´n Cient´ıfica y Te´cnica, Spain (PB95-0259) and the
J unta de Extremadura-Fondo Social Europeo (PRI97-
C175). One of us (F.R.C.) thanks the Spanish Ministerio
de Educacio´n y Cultura for a fellowship. The authors
also thank members of the technical departments of
Merck and Prolabo, Spain, for providing assistance with
the focused microwave reactor.
(6R)-6-(1′,2′,3′,4′-Tet r a -O-a cet yl-D-a r a bin o-t et r it ol-1′-
yl)-1,2-bis(eth oxyca r bon yl)-3-(4-m eth oxyp h en yl)-1,2,3,6-
tetr a h yd r o-1,2,3,4-tetr a zin e (10). This diastereomer was
1
isolated as an oil in 92% yield: [R]D +417° (c 0.5, CHCl3); H
NMR (CDCl3) δ 7.19 (d, J ) 8.8 Hz, 2H), 7.01 (d, J ) 3.5 Hz,
1H), 6.83 (d, J ) 8.8 Hz, 2H), 5.67 (dd, J ) 8.3 Hz, 1.6 Hz,
J O990442X